Restoration of blood to biochemical normalcy by treatment with ion exchange resins



United States Patent RESTORATION OF BLOOD TO BIOCHEMICAL NOR- MALCY BY TREATMENT WITH ION EXCHANGE RESINS John H. Gibbon, Jr., Media, Thomas F. Nealon, In,

Wynnewood, Jerome L. Sandler, Drexel Hill, and Robert Kunin, Yardley, Pa.; said Gibbon, Nealon, and Sandler assignors to Jefierson Medical College, Philadelphia, Pa., and said Kunin assiguor to Rohm & Haas Company, Philadelphia, Pa., a corporation of Delaware No Drawing. Filed June 14, 1962, Ser. No. 202,386

8 Claims. (Cl. 16778) This invention relates to the restoration to biochemical normalcy of whole blood whose pH is outside acceptable tolerances, and which contains excesses or deficiencies of ions that may cause serious physiological reactions.

More particularly, this invention is primarily concerned with the removal of potentially injurious ions from whole blood which is stored in acid-citrate-dextrose (ACD) solution, and elevating its pH from as low as 6.5 to about 7.4.

' Another object is to restore to biochemical normalcy blood which has been altered in patients having litle or no renal function.

It has long been the practice to use whole blood to replace the loss of circulating blood in patients, particularly those undergoing major surgical operations. As acceptable blood donors are not always available when needed, methods have been developed for preserving and storing blood at refrigerating temperatures, and the use of such stored blood in transfusion therapy has become quite common. Stored blood generally is useful for about twenty-one days, and where small amounts are needed this technique makes it possible to keep an adequate supply available for emergencies.

One of the necessary prerequisites to the storage of whole blood has been the prevention of the coagulation of the blood. Several methods are known for doing this, but the most Widely used technique is to employ a chemical anticoagulant such as diand tri-sodium cit-rate, heparin, etc.

As a general rule, blood is added to an aqueous solution of an anticoagulant in order to maintain the stability of the blood by preventing clotting, etc. Furthermore, blood normally is diluted with nonelectrolytic solutions to inhibit spontaneous hemolysis. Dextrose has been found to be an effective nonelectrolytic diluent, as it not only inhibits hemolysis but also serves as a substrate for glycolytic enzymes of erythrocytes in the blood. The dextrose, furthermore, appears to provide energy for the metabolism of the blood cells during the storage period.

The use of citrated blood, i.e. blood preserved with sodium citrate, may result in over-citration and upset the electrolytic balance of the blood, so that potassium, sodium, etc. diffiuse through the cell membranes and thereby increase the chances of cell rupture or hemolysis. In large volume blood transfusions, the use of citrated blood is contraindicated due to its upsetting the electrolytic balance and the possibility of hemolysis in the body.

As a matter of fact, blood preserved with ACD solution and stored in a refrigerator at C., in the conven tional manner, undergoes a number of changes which are potentially harmful to the ultimate recipient of such blood. In the first place there is a decrease in pH from the normal of 7.38-7.4 to about 6.5. Then there are increases in plasma hemoglobin, potassium, ammonium, pyruvate, lactate and phosphate. When such blood is administered to a patient in large amounts over even a short period of time cardiac arrest may result. Such blood is exceedingly dangerous to patients with diseased kidneys or livers. The elevated ammonium concentrations may produce hepatic coma in such cases. Hyperkalemia may result in electrocardiographic abnormalities, cardiac arrhythmias, or asystole.

Methods have been proposed for removing calcium ions from the blood by means of cation exchange resins in order to prevent coagulation of the blood. However, such methods will not remove calcium ions which are firmly bound to the citrate. Removal of the citrate before massive transfusion of ACD blood, already indicated for the reasons given above in order to avoid citrate intoxication, is further indicated in order to eliminate the calcium ions bound thereto. Removal of the citrate is readily accomplished by means of anion exchange resins. But the moment the citrate is removed the calcium ions are liberated and the blood becomes coagulable. To prevent clotting, an anti-coagulant such as heparin must be added as the citrate is removed. However, since heparin acts as an anion, much of it is removed by the anion exchange resins. Consequently, approximately a four-fold excess of heparin beyond the amount normally needed to prevent clotting usually is required.

Another problem which exists when calcium is removed is the fact that the same ion-exchange procedures normally employed for decalcification also cause substantially all of the potassium to be removed. Although stored whole blood develops increases in potassium content which may cause the patient to suffer serious complications, and this level of potassium therefore must be lowered, the level must not be premitted to go below the normal amount of about four milliequival'ents per liter (m.eq./l.) or else the blood will hemolyze and become unsuitable for transfusions. In fact, as has been disclosed in U.S. Patent 2,833,691, there is a critical ratio of potassium to sodium which must be maintained in the blood plasma and the blood cells in order to prevent increased cell fragility and avoid excessive hemolysis. This is done, according to the method of that patent, by using cation exchange resins buflered to a pH of 7.27.4, part of the resins being in the potassium salt form and the remainder in the sodium salt form.

The resins are employed in the process described in that patent to effect the necessary decalcification of fresh Whole blood immediately on withdrawal from the donor, while maintaining the relatively low potassium content of the blood substantially unchanged so as not to impair the normal sodium-potassium balance in the plasma and blood cells. In the present situation, however, the problem is far more complicated because, instead of treating fresh blood having potassium concentrations on the order of 4 m.eq./ 1., stored blood with potassium concentrations of about 25 m.eq./l. or more is being dealt with. As explained above, this potassium level has to be reduced to normal, but must not be eliminated entirely. This reduction, moreover, must be achieved Without altering the normal concentration of sodium ions which is about m.eq./l., while at the same time maintaining or lowering the level of calcium that is present in normal blood.

The problems described above are quite prevalent when ordinary direct transfusions are made of stored whole blood. But they are magnified to a much greater degree when very large quantities of stored blood are administered in large volumes. This occurs, for example, in operations such as those performed on the open heart using appartus known as a heart-lung machine.

This apparatus, which is illustratively shown and described in U.S. Patent 2,847,008, typically requires about six pints of whole blood to prime it. The amount of citrate in such a quantity of blood stored in ACD solution makes most surgeons hesitant to use it. As a substitute heparinized blood is used. Since such blood can only be used safely in the first 36-48 hours after its collection, special arrangements must be made to collect this blood either the day of the operation or the day before. Because of the possibility of hemorrhage during the open heart operation, heparinized blood in excess of the priming volume must also be collected. This is expensive, time consuming, and may cause critical delays in the performance of operations. Obviously, therefore, it is highly desirable to be able to use bank or stored blood to fill the heart-lung machine and to have a reserve of blood on hand for emergency use when that equipment is employed.

The critical need for using large amounts of blood from a blood bank, and for assuring that such blood is restored to its biochemical normalcy is thus dramatically made apparent. This is particularly the case since the use of such heart-lung machines continues to become more and more widespread as surgeons become more and more familiar with their utilization. Such is the need which is fully met by the present invention.

According to the present invention, whole blood which has been stored for up to about twenty-one days is passed through a mixture of at least one cation and one anion exchanger. Instead of just two such exchangers there may be employed three or four ion exchange resins chosen from a group of at least two cation exchange resins and two anion exchange resins. The cation exchangers consist of a strongly acidic and a weakly acidic resin; the anion exchangers consist of a strongly basic and a weakly basic resin. Illustrative of the strongly acidic cation exchangers is Amberlite 200, a macroreticular structured, styrene-divinylbenzene copolymer which has been sulfonated. Illustrative of the weakly acidic cation exchangers is Amberlite IRC50, which has carboxylic groups in the molecule, and is prepared by suspension copolymerizing a mixture of methacrylic acid and about 3 to divinylbenzene. The strongly basic anion exchanger is typified by Amberlite 402, a styrene-divinylbenzene copolymer which has been chloromethylated and subsequently aminated with trimethylamine. The weakly basic anion exchanger is typified by Amberlite XE168, a resin which is formed by reacting a polyamino compound containing at least one primary amino group with an insoluble, cross-linked copolymer of an ester of acrylic or methacrylic acid, divinylbenzene being the cross-linking agent. Amberlite 200, Amberlite IRC-SO, Amberlite 402 and Amberlite XE-168 are all commercial products of the Rohm & Haas Company, Philadelphia, Pa.

Actually, all of the ion exchangers useful in the practice of the present invention are available from a number of sources. The sulfonated materials, for example, are well known insoluble products which can exhange hydrogen for metal ions of soluble salts. They may be an insoluble phenolformaldehyde condensate having methylene sulfonic groups. They may likewise be styrene copolymers which are insolubilized by means of a crosslinking agent such as divinylbenzene or trivinylbenzene, and which contain sulfonic groups in nuclear positions. carbonaceous zeolites, prepared by sulfonation or sulfonation and oxidation of coals and lignites may be used, and the same applies to sulfonated condensed lignins. Details of the preparation of some sulfonated cation exchangers 4 may be found in US. Patents 2,195,196; 2,228,159, 2,228,- 2,366,007; and 2,597,438.

The quaternary ammonium resins are strongly basic materials which are capable of splitting salts, supplying hydroxyl ions or other anions. They are insoluble quaternary ammonium compounds in which the anion is a hydroxyl ion or the anion of an exceedingly weak acid, such as carbonic acid, including the bicarbonate ion, or boric acid. The N-substituents comprise first of all one or more resin-forming groups or parts and then small hydrocarbon or hydroxyalkylene groups. The functional group of these anion materials may be represented in its simplest form as where X is a hydroxyl group or anion of a weak acid, R"" is a copolymer chain to which the nitrogen is attached and R, R", and R' are small hydrocarbon or hydroxyalkyl groups, such as methyl, ethyl, propyl, butyl, benzyl, hydroxyethyl, hydroxypropyl, or the like. Typical quaternary ammonium ion exchange .resins are prepared from styrene by copolymerization with a cross-linking agent such as divinylbenzene, chloromethylation of the copolymer, and reaction of chloromethyl groups with a tertiary amine, such as trimethylamine, butyldimethylamine, benzyldimethylaminc, hydroxyethyldimethylamine, or the like. The chloride ion is replaced by-treatment with a base such as sodium hydroxide. Styrene may also be cross-linked with methylene groups, halomethylated, and then quaternized. Details of the preparation of such quaternary ammonium anion exchange resins are available in US. Patents 2,540,985, 2,591,573, and 2,614,099.

The carboxylic cation exchange resins are insoluble polymeric substances which contain the COOH groups as the functional group thereof. These .resins are obtainable from carboxylic acids (or their anhydrides) having an unsaturated linkage which permits them to enter into copolymers or heteropolymers with polymerizable substances including those which cause cross-linking. It is known, for instance, that maleic anhydride and styrene can be polymerized together and when there is present an unsaturated material having at least two non-conjugated double bonds, an insoluble resin results. The cross-linking material may be one such as divinylbenzene, trivinylbenzene, ethylene diacrylate, diallyl maleate or fumarate or itaconate, or the like. Another source of carboxylic exchangers is based on the copolymerization of acrylic or methacrylic acid and a polyunsaturated polymerizable substance such as diallyl maleate or fumarate or itaconate, allyl acrylate, allyl methacrylate, diallyl ether, ethylene dimethacrylate, divinylbenzene, or the like. The copolymers or heteropolymers are formed in the conventional way with the aid of a catalyst, such as benzoyl peroxide, lauroyl peroxide, tert.-perbenzoate, tert.-butylhydroperoxide, etc. The resin when formed may be crushed to a fine powder. The insoluble carboxylic resins may also be formed by emulsion polymerization and then precipitated as fine particles. Acid anhydride groups are converted to carboxyl groups by treatment of resins with an alkali or a strong acid. If alkali is used, the resulting salt form of the resin is readily converted to the acid form by washing it with acid. Details of the preparation of some carboxylic cation exchange resins may be found in US. Patents 2,340,110, 2,340,111, and 2,597,437.

Amino anion exchange resins are available from a number of sources. Phenols, aldehydes or ketones, and strongly basic amines can be condensed together by known methods to give insoluble resins which take up acids. Particularly useful resins of this sort are those made from polyphenylol compounds, such as di(hydroxyphenyl) methane or di(hydroxyphenyl) sulfone, formaldehyde, and polyalkylenepolyamines, such as triethylenetetramine or tetraethylenepentamine. Another type of anion exchange material is prepared by chloromethylating an insoluble styrene copolymer, such as one from styrene and divinylbenzene, and then reacting the chloromethylated product with an amine having hydrogen on the amino nitrogen. Polyamines such as diethylenetriamine, tetraethylenepentamine, and the like are particularly useful, although such amines as dimethylamine, diethylamine, methylamine, ethylamine, ethanolamine, and the like also give very useful amine anion exchange products. Another type of anion exchange resin is prepared from urea or melamine or the like, formaldehyde, and a polyamine, such as one of those named above or such a combination which includes guanidine or biguanide. Yet another type is based on phenylenediamine. As is known, m-phenylenediam'ine and formaldehyde give insoluble resinous materials which have capacity for taking up acids. Other types of amino exchangers can be used. These anion exchanger resins contain tertiary or secondary amine groups, or both, which have capacity for absorbing acids and yet do not have any marked tendency for splitting salts of strong bases and strong acids. Many of the amino anion exchange resins have been fully described in the art, e.g. US. Patents 2,591,574 and 2,675,359.

The following examples will illustrate the invention in more detail:

Example 1 A hemo-repellant plastic tube with a 100-mesh filter at the efiiuent end is filled with a mixture of about 50 gms. of Amberlite 200 in the sodium form, about 20 gms. of Amberlite 402 in the chloride form, and about 2.5 gms. of Amberlite IRC-SO in the hydrogen form together with about 2.5 gms. of Amberlite XE168 in the free base form. The resins are mixed thoroughly, homogeneously dispersed so that no clumps are evident, and kept moist at all times with a physiological saline solution.

Twenty units of human blood, stored for an average of 20.5 days, are passed over separate columns of this mixture of resins for periods of time ranging from 60 minutes to one and one-half hours. Samples of the blood are analyzed, before and after passage over the resins, for sodium, potassium, calcium, magnesium, chloride, ammonium, citrate, phosphate, lactate, pyruvate, plasma hemoglobin, and pH. The blood is passed over the resins A tube similar to that described in Example 1 is filled with a mixture of about 46 gms. of Amberlite 200 which is all in the sodium form except for 4 gms. which is in the potassium form, about 20 gms. of Amberlite 402 in the chloride form, about 3 gms. of Amberlite IRC5() of which one-third is in the hydrogen form and the remainder is in the sodium form, and about 3 gms. of

6 Amberlite XE-168 of which one-half is in the free base form and the remainder is in the chloride form. The resins are mixed thoroughly, homogeneously dispersed so that no clumps are evident, and kept moist at all times with a physiological saline solution.

Samples of 20 day old ACD human blood are passed through separate columns of this mixture of resins for about 69 minutes. The average analyses of twenty such samples, both before and after treatment, are as follows:

A resin pack similar to that described in Example 2 is used to treat ten units of stored ACD human blood 18 to 24 days old. Samples of each unit are taken for analysis before and after passage of the blood over the resins. Typical of the results are the following:

ACD Blood Normal Constituent Blood Before After Treatment Treatment pH 6.51 7. 26 7. 40 18. 20 0. 4. 00 581. 00 104. 00 150. 00 129. 10 2. (i0 0. 00 73. 30 110. 00 100.00

Examples 4-17 In each of these examples a tube similar to that described in Example 1 is filled with a mixture of approximately 75 grams of resins in the various combinations represented in Table I below. In Examples 4-10, the mixtures are formed from the first stated extremes of the percentages listed at the bottom of each column. For

' example, from Column A the resin mixture selected consists of 50%50% of sulfonated cation exchanger (1) and quaternary ammonium anion exchanger (2); from Column E the resin mixture selected consists of 49.5% of sulfonated cation exchanger (1), 49.5% of quaternary exchanger (2), 0.5% of carboxylic cation exchanger (3), and 0.5% of polyamine anion exchanger (4). In Examples 1117, the mixtures are formed from the other extremes of the percentages listed at the bottom of each column. For example, from Column B the resin mixture selected consists of of sulfonated exchanger (1), 15% of quaternary exchanger (2), and 15 of carboxylic exchanger (3); and from Column C the mixtures are formed from 70% of the sulfonated exchanger, 15 of the quaternary exchanger, and 15% of the carboxylic exchanger (3).

Separate samples of about 200 ml. of ACD stored blood, averaging 18 to 24 days old, are passed through the gm. ion exchange resin packs containing the mixtures as described above, each passage taking about 60 minutes. The analysis of each such sample is made before and after the treatment. The results are very similar to those described in Example 2, and closely approximate the composition of normal blood.

TABLE I.RESIN MIXTURES (PERCENT BASED ON ION EXCHANGE CAPACITIES) I Resin Type Column A Column A-l Column A-2 Column B Column C Column D Column E (l) sulfouated cation 10% K 0l0% K 0l0% K 0-l0% K 0 K 010% K 0l0% K.

exchanger. l0090% Na. l0090% Na. 100-90% Na. -l00-90% Na. l0090% Na. IOU-90% Na. 100-90% Na.

(2) Quaternary ammo- Cl 050% bicar- 050%lactate Cl Cl Cl Cl.

nium anion exbonate. changer. 5099.9% Cl". 5099.9% Cl.

(3) Carboxylic cation 50-75% Na 40-60% Na 060% Na.

exchanger. 50-25% H (50-40% H 100 i0% H.

(4) Polyamino anion ex- 50-75% free base. 40-60% free base. 0-60% chloride.

changer. 50-25% 01 (30-40% chloride 10040% free base.

Percent by weight of 50-80% of (1).. 50-80% of (l) 50-80% of (1) 49.570% of (1) 49.570% of (l) 39.555% of (1) 49.575% of (1). various resins in mix- 5020% 0f (2) 50-20% of (2) 50-20% of (2) 49.5l5% 0f (2) 49.5-% 0f (2) 59.5l0% of (2) 49.515% of (2). ture. 1.045% of (3) 1.015% of (4) 05-10% of (3) O.55% of (3). 0.5-% of (4) 05-55% of (4).

Example 18 Employing a tube similar to that described in Example 1, and using 72 grams of a resin mixture of the type identified as Column A-1 in Table I above in which the bicarbonate-chloride ratio is 1:1, 250 ml. of blood stored for two weeks is treated as explained in the foregoing examples. The citrate is lowered from about 93.0% to about 12.3% and the phosphate is lowered from about 4.81% to about 1.33%.

Example 19 Employing a tube similar to that described in Example 1, and using 56 grams of a resin mixture of the type identified as Column B in Table I above, 250 ml. of blood stored for two weeks is treated as explained in the foregoing examples. The resin column is made up of 27.5 gms. of sulfonated cation exchanger (1) in the sodium form, 2.5 gms. of sulfonated cation exchanger (1) in the potassium form, 20.0 gms. of quaternary ammonium anion exchanger (2) in the chloride form, 4.0 gms. of carboxylic cation exchanger (3) in the sodium form, and 2.0 gms. of carboxylic cation exchanger (3) in the hydrogen form. The potassium content is lowered from about 20.88% to about 4.50%.

Example 20 Employing a tube similar to that described in Example 1, and using 68 grams of a resin mixture of the type identified as Column C in Table I above, 250 ml. of blood stored for two weeks is treated as explained in the foregoing examples. The resin column is made up of gms. of sulfonated cation exchanger (1) in the sodium form, 3.0 gms. of sulfonated cation exchanger (1) in the potassium form, 20.0 gms. of quaternary ammonium anion exchanger (2) in the chloride form, 5.0 gms. of the polyamino anion exchanger (4), in the chloride form, and 5.0 gms. of the polyamino anion exchanger (4) in the free base form. The potassium content is lowered from about 18.0% to about 4.02%.

Example 21 Employing a tube similar to that described in Example 1, and using 74 gms. of a resin mixture of the type identified as Column D in Table I above, 250 ml. of blood stored for two weeks is treated as explained in the foregoing examples. The resin column is made up of 27.5 gms. of sulfonated cation exchanger (1) in the sodium form, 2.5 gms. of sulfonated cation exchanger (2) in the potassium form, 20 gms. of quaternary ammonium anion exchanger (2) in the chloride form, 4.0 gms. of carboxylic cation exchanger (3) in the sodium form, 2.0 gms. of carboxylic cation exchanger (3) in the hydrogen form, 9.0 gms. of the polyamino anion exchanger (4) in the sodium form, and 9.0 gms. of the polyamino anion exchanger (4) in the hydrogen form. The pH is elevated from about 6.57 to 7.37, and the potassium content is lowered from about 21.2% to about 4.1%.

It will be apparent that the invention may readily be varied considerably from the foregoing examples and still stay within the scope of this disclosure. Other combinations of resins and different weight percentages of each may be employed besides those illustratively described hereinabove. The ranges of each resin type given in Table I may be changed within the limits there shown. Still other modifications will suggest themselves to those skilled in the art.

While the above description and data have been mainly confined to the use of the present invention in restoring to biochemical normalcy blood bank blood, or stored blood to be used in transfusions, its application for the same purpose in cases of renal difficulties such as hyperkalemia should be apparent to those skilled in the art to which the invention pertains. The most serious threat to life in a patient whose kidneys have ceased to function is a high potassium concentration in the plasma. Heretofore, such patients have been treated by an artificial kidney in which the patients blood is pumped through a semi-permeable membrane immersed in a specially prepared bath. Now the potassium is lowered readily, as in one case from 9 m.eq./l. to 4 m.eq./'l., by the present invention. In this case the work of the kidneys was replaced by a 600 gm. column of a mixture of Amberlite 200 in the sodium form, Amberlite 402 in the chloride form, Amberlite IRC-SO in the hydrogen form, and Amberlite XE-168 in the free base form. The pH Was increased from 7.20 to 7.35, the calcium decreased from 8 m.eq./l., and the phosphate decreased from 10 mg. percent to 5 mg. percent.

We claim:

1. The method of restoring stored whole blood to biochemical normalcy, comprising, contacting the blood with a mixture of a strongly acidic cation exchanger and a strongly basic anion exchanger, at least about 39.5% but no more than by weight of which is the cation exchanger and at least about 10% by weight of which is the anion exchanger, from 0 to about 10% exchange capacity of the cation exchanger being in the potassium form with the remainder in the sodium form, and at least about half of the exchange capacity of the anion exchanger being in the chloride form.

2. The method of restoring stored whole blood to bio chemical normalcy, comprising, contacting the blood with a mixture of about 50 to 80% by weight of a sulfonated cation exchanger and about 50 to 20% by weight of a quaternary ammonium anion exchanger, from 0 to 10% exchange capacity of the cation exchanger being in the potassium form with the remainder in the sodium form, and the said anion exchanger being entirely in the chloride form.

3. The method of restoring stored whole blood to biochemical normalcy, comprising, contacting the blood with a mixture of about 50 to 80% by weight of a sulfonated cation exchanger and about 50 to 20% by weight of a quaternary ammonium anion exchanger, from 0 to 10% exchange capacity of the cation exchanger being in the potassium form with the remainder in the sodium form, and at least about 50% exchange capacity of the anion exchanger being in the chloride form with the balance being in the bicarbonate form. 1

4. The method of restoring stored whole blood to biochemical normalcy, comprising, contacting the blood with a mixture of about 50 to 80% by weight of a sulfonated cation exchanger and about 50 to 20% by weight of a quaternary ammonium anion exchanger, from to exchange capacity of the cation exchanger being in the potassium form with the remainder in the sodium form, and at least about 50% exchange capacity of the anion exchanger being in the chloride form with the balance being in the lactate form.

5. The method of restoring stored whole blood to biochemical normalcy, comprising, contacting the blood with a mixture of about 49.5 to 75% by weight of a sulfonated cation exchanger, about 49.5 to by weight of a qua-ternary ammonium anion exchanger, and about 1 to 10% by weight of a carboxylic cation exchanger, from 0 to 10% exchange capacity of the sulfonated cation exchanger being in the potassium form with the remainder in the sodium form, the exchange capacity of said anion exchanger being entirely in the chloride form, and the said carboxylic cation exchanger having its exchange capacity divided between about 50 to 75% in the sodium form and about 50 to 25% in the hydrogen form.

6. The method of restoring stored whole blood to biochemical normalcy, comprising, contacting the blood with a mixture of about 49.5 to 75 by weight of a sulfonated cation exchanger, about 49.5 to 15% by weight of a quaternary ammonium anion exchanger, and about 1 to 10% by weight of a polyamino anion exchanger, from 0 to 10% exchange capacity of the sulfonated cation exchanger being in the potassium form with the remainder in the sodium form, the exchange capacity of said quaternary ammonium anion exchanger being entirely in the chloride form, the said polyamino anion exchanger having its exchange capacity divided between about 50 to 75 in the free base form and about 50 to 25% in the chloride form.

7. The method of restoring stored whole blood to biochemical normalcy, comprising, contacting the blood with a mixture of about 39.5 to 55% by weight of a sulfonated cation exchanger, about 59.5 to 10% by weight of a quaternary ammonium anion exchanger, about 0.5 to 10% by weight of a carboxylic cation exchanger, and about 0.5 to 25% by weight of a polyamino anion exchanger, from 0 to 10% exchange capacity of the sulfonated cation exchanger being in the potassium form with the remainder in the sodium form, the exchange capacity of said quaternary ammonium anion exchanger being entirely in the chloride form, the exchange capacity of said carboxylic cation exchanger being divided be tween about 40 to in the sodium form and about 60 to 40% in the hydrogen form, and the exchange capacity of said polyamino anion exchanger being divided between about 40 to 60% in the free base form and about 60 to 40% in the chloride form.

8. The method of restoring stored Whole blood to biochemical normalcy, comprising, contacting the blood with a mixture of about 49.5 to by Weight of a sulfonated cation exchanger, about 49.5 to 15% by weight of a quaternary ammonium anion exchanger, about 0.5 to 5% by weight of a carboxylic cation exchanger, and about 0.5 to 5% by weight of a polyamino anion exchanger, from 0 to 10% exchange capacity of the sulfonated cation exchanger being in the potassium form with the remainder in the sodium form, the exchange capacity of said quaternary ammonium anion exchanger being entirely in the chloride form, the exchange capacity of said carboxylic cation exchanger being divided between 0 to 60% in the sodium form and to 40% in the hydrogen form, and the exchange capacity of said polyamino anion exchanger being divided between about 100 to 40% in the free base form and about 0 to 60% in the chloride form.

References Cited by the Examiner UNITED STATES PATENTS 2,673,827 3/1954 Kohlstaedt 16772 2,684,321 7/1954 Thurmon 16772 2,833,691 5/1958 'Klaas 167-78 2,879,166 3/1959 Wilcox 167-72 FOREIGN PATENTS 636,172 4/1950 Great Britain.

OTHER REFERENCES Calmon: Ion Exchangers in Organic and Biochemistry Inter-Science Pub.,-N.Y., 1957, pp. 628632; 688698.

McLaughlin: J. of Thora and Cardio-Vascular, 40:5, November 1960, pp. 602-10.

Muirhead: J. of Lab. & Clin. Med., vol. 33, 1948, pp. 841-844.

Sandler et a1.: J.A.M.A., 179:3, Jan. 20, 1962, pp. 201403.

Schechter: Surgery, Gym. and Obs., 108:1, Jan. 1959,

JULIAN S. LEVIIT, Primary Examiner.

FRANK CACCIAPAGLIA, JR., Examiner.

ANNA P. FAGELSON, VERA C. CLARKE,

Assistant Examiners. 

1. THE METHOD OF RESTORING STORED WHOLE BLOOD TO BIOCHEMICAL NORMALCY, COMPRISNG, CONTACTING THE BLOOD WITH A MIXTURE OF A STRONGLY ACIDIC CATION EXCHANGER AND A STRONGLY BASIC ANION EXCHANGER, AT LEAST ABOUT 39.5% BUT NO MORE THAN 80% BY WEIGHT OF WHICH IS THE CATION EXCHANER AND AT LEAST ABOUT 10% BY WEIGHT OF WHICH IS THE ANION EXCHANGER, FROM 0 TO ABOUT 10% EXCHANGE CAPACITY OF THE CATION EXCHANGER BEING IN THE POTASSIUM FORM WITH THE REMAINDER IN THE SODIUM FORM, AND AT LEAST ABOUT HALF OF THE EXCHANGE CAPACITY OF THE ANION EXCHANGER BEING IN THE CHLORIDE FORM. 